title: MicroRNA-223 controls  susceptibility to tuberculosis by regulating  lung neutrophil recruitment.
abstract: The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223(–/–) mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223(–/–) animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.
authors.forename: Anca
authors.initials: A
authors.lastname: Dorhoi
authors.forename: Marco
authors.initials: M
authors.lastname: Iannaccone
authors.forename: Maura
authors.initials: M
authors.lastname: Farinacci
authors.forename: Kellen C
authors.initials: KC
authors.lastname: Faé
authors.forename: Jörg
authors.initials: J
authors.lastname: Schreiber
authors.forename: Pedro
authors.initials: P
authors.lastname: Moura-Alves
authors.forename: Geraldine
authors.initials: G
authors.lastname: Nouailles
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Mollenkopf
authors.forename: Dagmar
authors.initials: D
authors.lastname: Oberbeck-Müller
authors.forename: Sabine
authors.initials: S
authors.lastname: Jörg
authors.forename: Ellen
authors.initials: E
authors.lastname: Heinemann
authors.forename: Karin
authors.initials: K
authors.lastname: Hahnke
authors.forename: Delia
authors.initials: D
authors.lastname: Löwe
authors.forename: Franca
authors.initials: F
authors.lastname: Del Nonno
authors.forename: Delia
authors.initials: D
authors.lastname: Goletti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Capparelli
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000818:Animals; D054405:Chemokine CCL3 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004198:Disease Susceptibility; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000235:genetics* / Q000276:immunology; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation
chemical_list: D054405:Chemokine CCL3; D054426:Chemokine CXCL2; D015850:Interleukin-6; D035683:MicroRNAs; D023063:Receptors, Interleukin-8B; C496534:Ccl3 protein, mouse; C404915:Cxcl2 protein, mouse; C525067:MIR223, human; C544877:MIRN223 microRNA, mouse